Identifying candidate modifier elements of a breast cancer risk associated allele Project Summary/Abstract: A woman's risk of developing breast cancer is influenced by genetic, epigenetic, and environmental factors. Up to 30-40% of the risk of developing breast cancer is likely to be inherited. Breast cancer genetics is complex. The factors controlling disease risk are high penetrant genes with risk alleles that are low in population frequency, and low penetrant modifier genes with risk associated alleles that are common in the population. Most of the genetic variation in breast cancer risk is unaccounted, and the majority of the genes influencing susceptibility to breast cancer are likely controlled by common genetic variation. The common single nucleotide polymorphism (SNP) rs889312 marks a low penetrant breast cancer risk associated allele on human chromosome 5 (Nature 447, 2007). The breast cancer risk associate gene and causal polymorphisms at this locus have not been identified. The human region is orthologous to rat mammary carcinoma susceptibility QTL, Mcs1b. The rat Mcs1b locus has been narrowed to 1.2 Mb using congenics. These experiments used the Wistar Furth (WF) strain, which is highly susceptible to 7,12- dimethylbenz[a]anthracene (DMBA)-induced mammary carcinomas, as the genetic background. The Mcs1b Copenhagen (COP) allele on a WF background conferred a 60% reduction in DMBA-induced mammary carcinoma development to WF.COP congenics that were COP-homozygous, and a 30% reduction to congenics that were COP/WF-heterozygous at Mcs1b. The objective of the proposed work is to use systems genetics in a model organism to identify quality candidate breast cancer risk genetic elements. This will be accomplished through the following specific aims: aim 1: fine map rat Mcs1b to a genomic interval less than 0.5 Mb by testing additional congenic lines carrying shorter segments of the Mcs1b locus as currently defined;aim 2: determine if the Mcs1b COP allele acts in an autonomous manner within the mammary gland by conducting rat mammary gland transplant experiments;and aim 3: identify and evaluate breast cancer candidate genes/genetic elements within rat Mcs1b by determining potential candidates and testing each to identify quality candidates. The final aim will be completed in stages that will incorporate comparative genomics, genetic and expression analyses, resequencing, and in vitro and in vivo validation of candidates. PUBLIC HEALTH RELEVANCE: Breast cancer is a complex disease, and the leading cause of death by cancer in US women aged 20- 59 years. Most common susceptibility genes and molecular genetic mechanisms contributing to breast cancer susceptibility are unknown. To work toward decreasing the incidence and mortality due to breast cancer, basic research toward better understanding of the genetic etiology of this complex disease is warranted. The proposed research uses a comparative genetic approach to accomplish this, and may also identify novel potential targets for breast cancer prevention.